Selective inhibitors to improve CPT-11 therapy

选择性抑制剂改善 CPT-11 治疗

• 批准号: 8458610
• 负责人: PHILIP M POTTER
• 金额: $ 29.55万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458610
• 关键词: Acetylcholinesterase; Adult; Adverse drug effect; Affinity; Animal Model; Animals; Antineoplastic Agents; Bile fluid; Biochemical; Biochemistry; Biological; Butyrylcholinesterase; Camptothecin; Carboxylic Ester Hydrolases; Cell Culture Techniques; Child; Cholesterol Esters; Cocaine; Colon Carcinoma; Complex Mixtures; Crystallography; Development; Diarrhea; Dose; Dose-Limiting; Engineering; Enzyme Inhibition; Enzymes; Evaluation; Goals; Half-Life; Heroin; Hour; Human; Hydrolysis; In Vitro; Incidence; Intestines; Knock-in Mouse; Lipids; Liver; Malignant Childhood Neoplasm; Malignant Neoplasms; Meperidine; Metabolism; Methods; Modeling; Mus; Pediatric Neoplasm; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plant Resins; Plasma; Poison; Procaine; Prodrugs; Property; Proteins; Quantitative Structure-Activity Relationship; Reagent; Resistance; Ritalin; SN-38; Severities; Small Intestines; Street Drugs; Testing; Therapeutic; Toxic effect; Type I DNA Topoisomerases; Water; Xenograft procedure; abstracting; analog; antitumor agent; base; benzil; cancer therapy; carboxylesterase; chemotherapeutic agent; design; esterase; improved; in vivo; inhibitor/antagonist; mouse model; novel; research study; response; small molecule; tumor

Abstract CPT-11 is a highly effective, camptothecin-based anticancer agent that is currently approved for the treatment of colon cancer. This compound is a prodrug and is activated by carboxylesterases to yield SN-38, a potent topoisomerase I poison. The dose limiting toxicity for CPT-11 is delayed diarrhea that occurs 48-96 hours following administration. This is thought to arise, in part, from direct activation of CPT-11, that is secreted in the bile, by a human intestinal carboxylesterase (CE) that is highly expressed in the small intestine. We hypothesize that by inhibiting this enzyme, reduced SN-38 will be produced from drug hydrolysis in the gut, thereby reducing the toxicity associated with CPT-11 treatment. The goals of this application are therefore to develop selective CE inhibitors that can be used to ameliorate the toxicity associated with CPT-11 administration. Highly potent, non-toxic small molecule inhibitors based upon the prototypical compound benzil have been identified, and we propose to develop these agents for use in inhibition of the human intestinal CE (hiCE). NMR, x-ray crystallography, medicinal chemistry, QSAR, biochemical and in vivo approaches will all be employed to validate the efficacy of suitable compounds The specific aims of this application are: 1) to determine the mechanism of CE inhibition by benzil; 2) to develop water-soluble analogues of benzil; 3) to assess the biochemical and biological properties of these compounds; and 4) assess their efficacy at modulating CPT-11-induced toxicity in a plasma esterase-deficient mouse model where hiCE is expressed in the mouse intestine. We believe that, if successful, these studies will provide reagents that can ameliorate the delayed diarrhea associated with CPT-11 administration, and potentially allow dose intensification of the drug. This would likely result in improved antitumor efficacy and furthermore, may also allow use of this CPT-11 against more resistant malignancies that demonstrate marginal response to this agent.

摘要 CPT-11是一种高效的、基于喜树碱的抗癌剂，目前已被批准用于治疗 结肠癌该化合物是一种前药，并被羧酸酯酶活化，产生SN-38，一种有效的 拓扑异构酶I中毒。CPT-11的剂量限制性毒性是48-96小时发生的迟发性腹泻 继行政。这被认为部分是由CPT-11的直接激活引起的，CPT-11是在细胞中分泌的。 胆汁，通过在小肠中高度表达的人肠羧酸酯酶（CE）。我们 假设通过抑制这种酶，减少SN-38将由肠道中的药物水解产生， 从而降低与CPT-11治疗相关的毒性。因此，本申请的目标是 开发可用于改善CPT-11相关毒性的选择性CE抑制剂 局基于原型化合物苯偶酰的高效无毒小分子抑制剂 已经确定，我们建议开发这些药物用于抑制人类肠道CE （hiCE）。NMR、X射线晶体学、药物化学、QSAR、生物化学和体内方法都将是 用于验证合适化合物的功效 本申请的具体目的是：1）确定苯偶酰抑制CE的机理; 2）确定 开发苯偶酰的水溶性类似物; 3）评估这些化合物的生物化学和生物学特性 化合物;和4）评估它们在调节血浆酯酶缺乏的受试者中CPT-11诱导的毒性方面的功效。 小鼠模型，其中hiCE在小鼠肠道中表达。 我们相信，如果成功的话，这些研究将提供可以改善延迟性腹泻的试剂。 与CPT-11给药相关，并可能允许药物的剂量强化。这可能会 导致改善的抗肿瘤功效，并且此外，还可以允许使用该CPT-11对抗更多的 对该药剂表现出边际应答的耐药恶性肿瘤。

项目成果

Modulation of esterified drug metabolism by tanshinones from Salvia miltiorrhiza ("Danshen").

• DOI: 10.1021/np300628a
• 发表时间: 2013-01-25
• 期刊: Journal of natural products
• 影响因子: 5.1
• 作者: Hatfield MJ;Tsurkan LG;Hyatt JL;Edwards CC;Lemoff A;Jeffries C;Yan B;Potter PM
• 通讯作者: Potter PM

Challenges and Opportunities with Non-CYP Enzymes Aldehyde Oxidase, Carboxylesterase, and UDP-Glucuronosyltransferase: Focus on Reaction Phenotyping and Prediction of Human Clearance.

• DOI: 10.1208/s12248-016-9962-6
• 发表时间: 2016-11
• 期刊: The AAPS journal
• 作者: Argikar UA;Potter PM;Hutzler JM;Marathe PH
• 通讯作者: Marathe PH

Carboxylesterase inhibitors.

• DOI: 10.1517/13543776.2011.586339
• 发表时间: 2011-08
• 期刊: Expert opinion on therapeutic patents
• 影响因子: 6.6
• 作者: Hatfield MJ;Potter PM
• 通讯作者: Potter PM

In Silico Design and Evaluation of Carboxylesterase Inhibitors.

• DOI: 10.1584/jpestics.r10-06
• 发表时间: 2010
• 期刊: Journal of pest science
• 影响因子: 4.8
• 作者: Stoddard SV;Yu X;Potter PM;Wadkins RM
• 通讯作者: Wadkins RM

Structure-activity relationships of substituted 1-pyridyl-2-phenyl-1,2-ethanediones: potent, selective carboxylesterase inhibitors.

• DOI: 10.1021/jm101101q
• 发表时间: 2010-12-23
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Young BM;Hyatt JL;Bouck DC;Chen T;Hanumesh P;Price J;Boyd VA;Potter PM;Webb TR
• 通讯作者: Webb TR